Opioid Guidelines.indd - Vancouver Coastal Health

a Guideline for the
Clinical Management of
Opioid Addiction
Published 2015
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Vancouver Coastal Health & Providence
Health Care Opioid Use Disorder
Treatment Guideline Committee
Dr. Keith Ahamad, MD
Addiction Medicine Consult Team, St. Paul’s Hospital, Providence Health Care;
Addiction Medicine Physician, Vancouver Detox
Dr. Cassandra Djurfors, MD
Medical Coordinator, Pender Community Health Centre, Vancouver Coastal Health
Dr. Ronald Joe, MD
Associate Medical Director, Addiction Services, Vancouver Coastal Health
Dr. Venu Karapareddy, MD
Addiction Psychiatrist, Vancouver Coastal Health
Ms. Mary Marlow, RPN
Mental Health and Substance Use Services, Vancouver Coastal Health
Dr. Garth McIver, MD
Addiction Physician (retired) and Medical Director (retired), VCH Addiction Services
Dr. Mark McLean, MD
Physician Lead, Addiction Medicine Consult Team, St. Paul’s Hospital, Providence Health Care;
Addiction Medicine Physician, Vancouver Detox
Dr. Daniel Paré, MD
Medical Coordinator, Downtown Community Health Centre – Primary Care and Addiction
Physician, Assertive Community Treatment (ACT) Team, Vancouver Coastal Health
Dr. Christy Sutherland, MD
Medical Director, Portland Hotel Society
Dr. Kenneth Tupper, PhD
British Columbia Ministry of Health
Dr. Evan Wood, MD, PhD (Committee Chair)
Medical Director, Community Addiction Services, Vancouver Coastal Health/Providence Health
Care; Co-director, Urban Health Research Initiative, BC Centre for Excellence in HIV/AIDS;
Professor of Medicine, UBC
Conflicts of interest
None of the committee members had conflicts of interest to declare.
Acknowledgements
Dr. Rolando Barrios, Senior Medical Director, Vancouver Coastal Health
Ms. Laura Case, Chief Operating Officer, Vancouver Coastal Health
Ms. Anne McNabb, Director Mental Health and Addiction Urban Site Lead,
Vancouver Coastal Health
Mr. Andrew MacFarlane, Director Mental Health and Addiction Inner City and Regional
Program Director Mental Health and Addiction Program
The B.C. Centre for Excellence in HIV/AIDS
The authors thank Ms. Pauline Voon (PhD Candidate) for primary research and writing
assistance in preparing this document, as well as Ms. Deborah Graham and Ms. Emily Wagner
for their editorial and administrative assistance, and Ms. Lianlian Ti and Mr. James Nakagawa
for their assistance with document layout and design.
Peer Reviewers
Dr. Rashmi Chadha, MBChB, MScCH, CCFP, MRCGP: Addiction and Family Medicine,
Physician, Vancouver Coastal Health
Dr. Ramm Hering, MD, CCFP, MSc, Dip PH: Addiction and Family Medicine Physician,
Pandora Clinic, Victoria, BC
Dr. P. Todd Korthuis, MD, MPH: Associate Professor of Medicine and Public Health–
Preventive Medicine, Oregon Health and Science University
Dr. Scott MacDonald, MD: Physician Lead, Providence Crosstown Clinic
Dr. David C. Marsh, MD, CCSAM: Deputy Dean, Professor and Associate Dean Community
Engagement, Northern Ontario School of Medicine
Dr. Christian G. Schütz MD, PhD, MPH, FRCPC: Research and Education Clinical Manager,
Burnaby Centre for Mental Health and Addictions
Ms. Kathleen Perkin: Manager, Harm Reduction Policy, British Columbia Ministry of Health
From Grief to Action Board Members
BC Association of People on Methadone (BCAPOM) Board Members, shared for feedback on
August 20, 2015
Ms. Mae Burrows, Family Advocate
Table of contents
Executive summary...................................................................................................................1
Summary of recommendations................................................................................................. 3
Introduction..............................................................................................................................4
Guideline development.............................................................................................................4
Possible treatment options........................................................................................................5
Literature review.......................................................................................................................5
I
Withdrawal management strategies.................................................................................6
II
Agonist treatments..........................................................................................................9
III
Alternative agents.......................................................................................................... 13
IV
Combination approaches and movement between approaches......................................14
V
Psychosocial supports....................................................................................................16
Expert guideline...................................................................................................................... 17
Appendices
Appendix 1: Induction and dosing guidelines for buprenorphine/naloxone...........................20
Appendix 2: Dosing recommendations for slow-release oral morphine (SROM)....................23
Appendix 3: Take-home dosing recommendations for oral agonist therapy.........................25
References.............................................................................................................................. 27
While the Vancouver Coastal Health Authority (“VCH”) and Providence Health Care (“PHC”) have made every effort
to ensure the accuracy of the information contained in this treatment guideline, please note that the information
is provided “as is” and that VCH and PHC make no representation or warranty of any kind, either expressed or
implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest
extent possible under applicable law, VCH disclaims and will not be bound by any express, implied or statutory
representation or warranty (including without limitation representations or warranties of title or non-infringement).
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Executive summary
O
pioid use disorder is one of the most challenging forms of addiction facing the health
care system in British Columbia. Despite an excellent guideline by the College of
Physicians and Surgeons of British Columbia regarding the safe use of methadone maintenance
treatment (MMT), there remains a need for an evidence-based guideline articulating the full
range of therapeutic options for the optimal treatment of adults and young adults with varying
presentations of opioid use disorder. This lack of a comprehensive guideline has been a challenge
for Vancouver Coastal Health (VCH) and the provincial health system, and has resulted in a lack of
awareness and use of the full armamentarium of medical and psychosocial treatments available
for managing opioid dependence among health care providers in substance use services and the
addiction care continuum.
To address this, an interdisciplinary
committee comprising individuals from
VCH, Providence Health Care and the
Ministry of Health developed the following
expert guidelines. These guidelines were
subsequently peer-reviewed by patient
groups, local and international experts in
the field. The recommendations in these
guidelines are based on a systematic
review and use of a traditional hierarchy
of evidence whereby meta-analysis of
randomized clinical trials was given the most
weight, followed by individual clinical trials,
observational reports and expert opinion.
While this guideline supports the diversity of
possible treatments available for individuals
presenting with opioid use disorder, it
strongly recommends against a strategy
involving only withdrawal management
(often referred to as “detox”), since this
approach has been associated with elevated
rates of infections such as HIV and hepatitis C, elevated rates of overdose deaths in comparison
to providing no treatment, and nearly universal relapse when implemented without plans for
transition to long-term evidence-based treatment. However, this guideline acknowledges the
1
importance of strengthening the residential treatment system with a view to aiding individuals
seeking long-term cessation of opioid use who do not wish to initially pursue pharmacological
treatment for opioid dependence, but may still wish to use other various pharmacotherapies
for symptom management during withdrawal. In addition, this guideline strongly endorses
the use of buprenorphine/naloxone as a preferred first-line treatment when opioid
substitution pharmacotherapy is being considered for the treatment of opioid use disorder
and contraindications have been ruled out. This recommendation is in line with the growing
body of research suggesting that buprenorphine has a six times greater safety profile than
methadone in terms of overdose risk, in addition to other comparative advantages. Notably,
methadone has recently been reported to be involved in approximately 25% of prescriptionopioid-related deaths in British Columbia. However, this guideline also endorses the use of
methadone as a first-line therapy when pharmacotherapy is appropriate and contraindications
to buprenorphine/naloxone exist, and supports the use of methadone as a second-line option
when buprenorphine/naloxone treatment proves to have limitations or is initially ineffective.
Beyond these three possible first-line or second-line treatment approaches, this guideline also
reviews the international evidence regarding the use of alternative pharmacotherapies for
the treatment of opioid use disorder, including long-acting oral morphine as well as injectable
opioid medications that must be provided via witnessed injection in a structured and supervised
setting.
Finally, this guideline recognizes that most individuals will benefit from the ability to move
between treatments, depending on the individual’s initial presentation, comorbidities,
treatment preferences and response to treatment. This includes intensification (e.g., initiating
a pharmacotherapy when a non-pharmacotherapy-based strategy is unsuccessful) as well as
routine strategies to de-intensify treatment (e.g., transition from methadone to buprenorphine/
naloxone) when patients are effectively treated and wish to transition to treatments that allow
for more flexible take-home dosing (e.g., buprenorphine/naloxone).
With the greater incorporation of evidence-based medicine principles into the treatment of
opioid use disorder through adherence to data-driven therapeutic guidelines, there is substantial
potential to improve systems of treatment for opioid use disorder and significantly reduce
the burden of disease and health and social service costs associated with untreated opioid
addiction. In order to address these costs, while recognizing the finite funding available for
health services, prioritization and proportionate funding should be reasonably allocated toward
the recommendations laid out in this guideline.
2
Summary of recommendations
Recommendation
For more
Quality of
Strength of
information
evidence* recommendation* see page…
Approaches to avoid
Withdrawal management alone (i.e., detox without
transition to longer term treatment) is not recommended,
since this approach has been associated with elevated rates
of HIV infection and overdose death.
⊕⊕⊕
Moderate
Strong
6
Initiate opioid agonist treatment with buprenorphine/
naloxone whenever feasible to reduce toxicities and
facilitate safer take home dosing.
⊕⊕⊕⊕
High
Strong
10
Initiate opioid agonist treatment with methadone when
treatment with buprenorphine/naloxone is not preferable
(e.g., challenging induction, high risk for drop-out).
⊕⊕⊕⊕
High
Strong
9
When opioid withdrawal is being medically supervised,
this can generally be safely done on an outpatient rather
than inpatient basis but should include ongoing addiction
treatment.
⊕⊕⊕
Moderate
Strong
6–7
⊕⊕⊕⊕
High
Strong
14
For individuals with successful and sustained response to
methadone desiring treatment simplification, consider
transition to buprenorphine/naloxone.
⊕⊕⊕
Moderate
Strong
14
For individuals with successful and sustained response to
agonist treatment desiring medication cessation, consider
slow taper over 12 months.
⊕⊕⊕
Moderate
Strong
6
Psychosocial supports may be routinely offered in
conjunction with pharmacological treatment.
⊕⊕⊕
Moderate
Conditional
16
⊕⊕
Low
Weak
6, 14
Possible first-line treatment options
Adjunct or alternative treatment options
For individuals responding poorly to buprenorphine/
naloxone, transition to methadone.
For patients wishing to avoid initial treatment with an opioid
agonist therapy, provide outpatient opioid agonist taper
(preferably methadone or buprenorphine/naloxone), with
subsequent immediate referral to intensive outpatient or
residential addiction treatment. Oral naltrexone can be
considered as an adjunct in this context.
* GRADE criteria were used to ascertain and describe the quality of evidence (possible categories include: high,
moderate, low, very low) and strength of recommendation (possible categories include: strong, conditional, weak).1
3
Introduction
While Canadian estimates are lacking, opioid use disorder is estimated to affect approximately 1.4%
of Americans.2 Opioid use disorder may involve the use of illicitly obtained opioids (e.g., heroin) or,
increasingly, diverted or misused prescription opioid medications. As a result, opioid use disorder is
often a chronic illness associated with elevated rates of morbidity and mortality.
British Columbia has benefited from a well established methadone maintenance program stewarded by
the College of Physicians and Surgeons of British Columbia.3,4 The Methadone Maintenance Committee,
which oversees the methadone maintenance program, has developed an expert guideline for the use
of methadone maintenance treatment that is periodically updated and is an excellent resource for
physicians wishing to prescribe methadone for opioid use disorder.5
However, in recent years, a number of additional opioid agonist treatment options have emerged for
the treatment of opioid addiction. Coinciding with this, evidence-based reviews have increasingly
described the benefits, side-effect profiles and safety concerns surrounding the various approaches
to the treatment of opioid use disorder. This literature, which is reviewed in detail below, enables the
development of strategies for the treatment of opioid use disorder that employ different approaches
based on individual patient circumstances and comorbidities and recognize that treatment can be
intensified or simplified depending on short- and long-term response to treatment.
To address the health care needs within the VCH catchment area, and to best address the needs of
patients with opioid use disorder in an evidence-based, cost-effective way, an expert panel was
convened by VCH to discuss this literature and propose a guideline for VCH with respect to the optimal
treatment and care of individuals with opioid addiction. What follows is a description of the literature
supporting these recommendations and ultimately a description of the treatment pathways being
recommended by this panel for use by health care providers across VCH. These guidelines relate to the
clinical management of established opioid addiction among adults and youth with opioid use disorder,6
while treatment options for specialized populations affected by opioid use disorder (e.g., pregnant
women) are beyond the scope of this guideline.
Guideline development
The recommendations in these guidelines are based on a systematic review and use of a traditional
hierarchy of evidence whereby meta-analysis of randomized clinical trials was given the most
weight, followed by individual clinical trials, observational reports and expert opinion. In addition,
the literature reviewed in this guideline was summarized as per the criteria set out by the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) Working Group,1 which is a system
that has been applied to high-level guideline and systematic review development processes, including
all policies and guidelines developed by the World Health Organization.7 The GRADE system takes into
consideration both the quality of evidence (high, moderate, low or very low, with quality determined by
both study design and other important factors such as weighing risks versus benefits, likelihood of bias,
or limited or inconsistent results) and the strength of recommendation (strong, conditional, or weak).
All members of the VCH Opioid Use Disorder Treatment Guideline Committee reviewed and reached a
majority agreement on the guidelines and recommendations after several rounds of revision.
4
Possible treatment approaches
Possible treatment options considered included: withdrawal management from opioid drugs and an
outpatient or residential treatment referral; opioid agonist therapy, particularly with methadone,
buprenorphine/naloxone or other agonists; and opioid antagonist medications such as naltrexone.
The guideline also considered the research regarding the integration of psychosocial treatments and
supports for opioid use disorder. Although evidence presented here is generally extrapolated from
studies conducted in adult populations, with this caveat, the consensus of the committee is that
recommendations are relevant and applicable to adult and young adult populations.
Literature review
Table 1. Treatment options for opioid use disorder
Agonist Therapies
Withdrawal Management 1–3
Tapered methadone, buprenorphine,
or alpha-2 adrenergic agonists
⁺⁄₋ psychosocial treatment 4
⁺⁄₋ residential treatment
⁺⁄₋ oral naltrexone 5
LOW
If opioid use continues,
consider treatment intensification »
Buprenorphine/
naloxone 6
(preferred)
Methadone 7,8
TREATMENT INTENSITY
Alternative Approaches
Slow-release
oral morphine 9
Diacetylmorphine 10
HIGH
Where possible,
« simplify treatment
Citations
1.
2.
3.
4.
5.
Amato L, Davoli M, Minozzi S, Ferroni E, Ali R, Ferri M.
Methadone at tapered doses for the management of opioid
withdrawal. Cochrane Database Syst Rev 2013;2:CD003409.
Gowing L, Ali R, White JM. Buprenorphine for the management
of opioid withdrawal. Cochrane Database Syst Rev
2009:CD002025.
Gowing L, Farrell MF, Ali R, White JM. Alpha2-adrenergic
agonists for the management of opioid withdrawal. Cochrane
Database Syst Rev 2014;3:CD002024.
Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and
pharmacological treatments versus pharmacological treatments
for opioid detoxification. Cochrane Database Syst Rev
2011:CD005031.
Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A.
Oral naltrexone maintenance treatment for opioid dependence.
Cochrane Database Syst Rev 2011:CD001333.
6.
Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine
maintenance versus placebo or methadone maintenance
for opioid dependence. Cochrane Database Syst Rev
2014;2:CD002207.
7. Mattick RP, Breen C, Kimber J, Davoli M. Methadone
maintenance therapy versus no opioid replacement therapy
for opioid dependence. Cochrane Database Syst Rev
2009:CD002209.
8. Faggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone
maintenance at different dosages for opioid dependence.
Cochrane Database Syst Rev 2003:CD002208.
9. Ferri M, Minozzi S, Bo A, Amato L. Slow-release oral morphine
as maintenance therapy for opioid dependence. Cochrane
Database Syst Rev 2013;6:CD009879.
10. Ferri M, Davoli M, Perucci CA. Heroin maintenance for chronic
heroin-dependent individuals. Cochrane Database Syst Rev
2011:CD003410.
5
I Withdrawal management* strategies
ALPHA-2 ADRENERGIC AGONISTS
Compared to placebo, alpha-2 adrenergic agonists (e.g., clonidine) have been found to be effective
for opioid withdrawal management in terms of a lesser likelihood of severe withdrawal symptoms and
higher probability of completing treatment.8
Signs and symptoms of withdrawal appear to both occur and resolve earlier with alpha-2 adrenergic
agonists. The chances of completing treatment of withdrawal are similar between alpha-2 adrenergic
agonists and methadone, but alpha-2 adrenergic agonists tend to require shorter
treatment durations. However, compared to methadone tapers, alpha-2 adrenergic
agonists are somewhat less effective in mitigating withdrawal symptoms, and
The majority of
are more likely to present adverse effects such as hypotension.8
patients still relapse
to opioid use if a
strategy involving
only withdrawal
management is
employed.
AGONIST TAPER – METHADONE9
Tapering off opioids with methadone appears to reduce the severity of
withdrawal symptoms, but the majority of patients still relapse to opioid
use if a strategy involving only withdrawal management is employed.10
Methadone at tapered doses does not appear to differ from other
pharmacological treatments (e.g., adrenergic agonists, other opioid agonists)
in terms of treatment completion, sustained abstinence, severity of withdrawal
symptoms, or adverse effects. Compared to placebo, tapered methadone appears to
be associated with less severe withdrawal symptoms and lower rates of drop-out.9
It is important to note that wide variations in the literature were a major limitation when comparing
tapered methadone to other treatments (e.g., different studies assessed different outcomes of
withdrawal management using methadone versus other treatments, which did not allow for exact
comparisons between treatment approaches in certain contexts).9
AGONIST TAPER – BUPRENORPHINE/NALOXONE11
Similar to tapering off opioids with methadone, agonist taper involving buprenorphine/naloxone
appears to reduce the severity of withdrawal symptoms, but the majority of patients still relapse to
opioid use if a strategy involving only withdrawal management is employed. For instance, patients in the
Prescription Opioid Addiction Treatment Study demonstrated significantly lower sustained abstinence
rates eight weeks after tapering off buprenorphine/naloxone (8.6%) compared to success rates during
buprenorphine/naloxone treatment (49.2%).12
At least in inpatient settings, buprenorphine appears to be more advantageous compared to
methadone, in terms of offering faster symptom relief and higher rates of treatment completion. There
does not appear to be a significant difference in terms of withdrawal symptom severity for individuals
managed with buprenorphine compared to methadone.11
Sometimes referred to as “detoxification” or “detox”
*
6
Buprenorphine is also more effective than alpha-2 adrenergic agonists (e.g., clonidine), as it appears
to offer more effective relief of withdrawal symptoms and to promote longer retention in treatment
and greater likelihood of completing treatment.11 There does not appear to be a significant difference
between buprenorphine and alpha-2 adrenergic agonists in terms of the incidence of adverse effects,
except in the case of clonidine, which may be associated with greater drop-out due to adverse effects.11
OTHER CONSIDERATIONS FOR TREATMENT USING WITHDRAWAL MANAGEMENT ONLY
The lack of effectiveness of treatment using withdrawal management alone (e.g., without transition
to long-term treatment) often rapidly leads to high rates of relapse post-treatment, which, in turn,
increases the risk of HIV transmission, morbidity and mortality.13,14 As the first point of engagement
in clinical care, opioid withdrawal management can serve an important role as a bridge to further
treatment, but is not recommended unless a strategy is in place for referral to ongoing intensive
outpatient or residential treatment.
Specifically, a meta-analysis found higher HIV incidence among individuals undergoing withdrawal
management only compared with individuals receiving no treatment.13 Other past research has shown
that individuals who have received inpatient opioid withdrawal management are at increased risk
of death from drug overdose compared to those who received no treatment.14 This phenomenon is
believed to be due to loss of tolerance to opioids and is consistent with the increased risk of fatal opioid
overdose observed following release from prison.15 Furthermore, relapse is common among patients
undergoing withdrawal management only, with a significantly lower rate of abstinence at discharge
(12%) compared to abstinence rates associated with other opioid treatment approaches (18 to 21%).10,16
In order to reduce the risk of fatal overdose among high-risk patients, take-home naloxone prescriptions
ought to be considered as a safe and effective fatal overdose prevention strategy.17,18
PSYCHOSOCIAL SUPPORTS PROVIDED WITH WITHDRAWAL MANAGEMENT
Psychosocial supports appear to be beneficial adjuncts to opioid withdrawal management.19 When
offered in addition to pharmacologically-supported withdrawal management (i.e., taper with opioid
medication), psychosocial therapies such as contingency management and psychotherapeutic
counselling are effective in terms of improving treatment retention and completion, sustaining
abstinence from illicit opioids, and reducing opioid use during treatment. However, there is currently
limited evidence due to small study sample sizes and varying assessment and outcome measurements.
There is also insufficient evidence to favour any specific psychosocial approach.19 Therefore, further
research and patient-specific approaches are needed with regard to psychosocial treatments.
Importantly, while psychosocial treatments may improve rates of treatment retention and completion,
psychosocial treatments provided during opioid withdrawal management likely do not protect against
the elevated risk of HIV infection or fatal overdose if withdrawal management alone is pursued, due to
high rates of relapse post-treatment and the negligible benefit of withdrawal management alone.12–14,20
RESIDENTIAL TREATMENT
There are no systematic reviews or meta-analyses considering the impacts of residential treatment
programs for individuals with opioid use disorder. The overall dearth of evidence does not mean
7
residential treatment is ineffective, but rather that the intervention has been under-studied, thus
requiring review of individual studies. There are also no large clinical trials comparing residential
treatment to other interventions and there are few rigorous evaluations that would help identify specific
characteristics of effective residential treatment programs or patient characteristics that may predict
appropriateness of residential treatment referral.
Among the evaluations that have specifically examined the impacts of residential treatment for opioid
dependence, relapse has been shown to be relatively common among clients referred to residential
treatment for opioid use disorder. Smyth et al. (2010) evaluated patients with opioid use disorder
admitted to a six-week residential treatment program with methadone withdrawal management,
psychosocial therapies (e.g., group, individual and/or family therapy) and an aftercare component. The
study found that 80% reported relapse within one month, of whom 59% relapsed within one week of
discharge.21 Additionally, younger age, failure to complete six weeks of treatment, greater heroin use
prior to treatment, history of injecting and a failure to enter aftercare were associated with a shorter
time to relapse.
In a study conducted among clients recruited from over 20 residential treatment programs (using
methadone, lofexidine or codeine for withdrawal management, with the goal of achieving abstinence
from opioids) in the United Kingdom,22 clients demonstrated improvements in terms of reduced
injecting, sharing of injection equipment, heavy drinking and criminal behaviour after residential
treatment.23 A follow-up study of this cohort found that approximately 57% of clients used heroin within
30 days of discharge from residential treatment.24 Longer stays in treatment were predictive of better
one-year outcomes.
Studies of residential treatment in the United States also present varied results. When data up to
42 months after trial enrolment were considered in the Prescription Opioid Addiction Treatment Study,
it is noteworthy that the greatest predictor of abstinence was being on agonist therapy, but also that
more than 30% of patients diagnosed with opioid addiction were abstinent from opioids and not on
agonist therapy.25 One longitudinal study found similar rates of treatment retention, completion and
patient satisfaction among individuals in outpatient and residential treatment programs.26 Similarly, one
randomized trial found that patients enrolled in residential treatment for less than seven weeks showed
no significantly different outcomes compared to patients who did not receive any type of treatment.27
For patients enrolled in residential treatment for more than seven weeks, improved outcomes were
observed, including increased likelihood of employment or enrolment in school, decreased likelihood
of criminal conviction or incarceration, and decreased likelihood of heroin use, compared to patients
who did not receive any type of treatment.27 An additional study found that a four-week residential
treatment program significantly decreased several maladaptive cognitive and behavioural patterns that
may contribute to ongoing substance use problems in opioid-dependent adults.28
Another randomized clinical trial found that a combination of community reinforcement and family
training in addition to residential withdrawal management using buprenorphine, particularly when
involving the adult patient’s parents, was positively and significantly associated with improved
retention in treatment and reductions in opioid and other drug use.29 Therefore, patients may benefit
from residential treatment that involves fostering family and other social connections.
8
Importantly, concerns regarding fatal overdose as a result of loss of tolerance during residential
treatment without agonist therapy should be considered. In this regard, there is evidence from a national
UK-based study that residential treatment is associated with reduced rates of overdose.30 Nevertheless,
health care providers must be vigilant in assessing for risk of relapse and consider implementing
strategies to reduce the risk of fatal overdose (e.g., take-home naloxone, sterile syringe provision,
starting opioid agonist therapy), given the known protective effects of these strategies against opioid
use and related harms, particularly when individuals leave or are discharged from residential treatment
and are at high risk of relapse.31
II Agonist maintenance treatments
Overall, as described below, opioid agonist maintenance treatments have been shown to be superior
to withdrawal management in terms of retention in treatment, sustained abstinence from opioid use,
and reduced risk of morbidity (e.g., HIV transmission) and mortality. The choice of agonist treatment
depends on several patient-specific factors such as initial presentation, comorbidities (e.g., liver disease,
prolonged QT), treatment preference, and response to treatment, as discussed below. Regardless
of type of treatment administered, agonist maintenance treatment should incorporate long-term
addiction monitoring, including regular followup, urine drug screens and mental health care.
METHADONE
Methadone has been shown to be significantly
more effective than non-pharmacological
outpatient treatment approaches in terms
of treatment retention and suppression of
heroin use.32 Methadone at higher doses (e.g.,
between 60–120 mg/day or higher) is more
effective than lower doses in terms of treatment
retention and reducing heroin and cocaine use
during treatment.33,34 Methadone maintenance
treatment has also been shown to reduce
injection risk behaviours and the overall risk
of hepatitis C and HIV infection among people
who inject drugs.13,35,36 Furthermore, among HIVpositive individuals, engagement in methadone maintenance therapy is independently associated with
increased adherence to antiretroviral therapy and improved virologic outcomes (e.g., lower HIV viral
loads, higher CD4 counts), particularly at higher doses (≥100 mg/day).37–39 While methadone dosing should
be based on clinical judgment determined individually due to differences in individual metabolism,
comorbidities (e.g., liver disease, prolonged QT) and drug interactions,40 most studies have suggested
that patients who take daily doses of 80 mg/day or higher have optimal treatment outcomes33 and
that doses well above 120 mg/day may be required to produce full opioid blockade and fully suppress
withdrawal.41,42 Challenges with withdrawal have been reported with the recent transition in PharmaCare
9
coverage from methadone to Methadose™ in BC, likely related to change intolerance.43 Where possible,
providing methadone to those struggling with Methadose™ may have advantages.
For induction and dosing guidelines for methadone maintenance treatment, practitioners are advised
to refer to the College of Physicians and Surgeons of BC’s Methadone Maintenance Program: Clinical
Practice Guideline.5
BUPRENORPHINE/NALOXONE
Buprenorphine is superior to placebo in terms of greater treatment retention at doses greater than
2 mg/day, and greater suppression of illicit opioid use at doses greater than 16 mg/day.44 Compared to
methadone, buprenorphine at low doses (≤ 6 mg/day) is less effective in terms of treatment retention
compared to low doses of methadone (≤ 40 mg/day). At medium and high doses, buprenorphine does
not markedly differ from methadone in terms of treatment retention. Buprenorphine and methadone
are equally effective in terms of reducing of illicit opioid use.44
For induction and dosing guidelines for buprenorphine/naloxone maintenance treatment, refer to
Appendix 1.
COMPARING METHADONE TO BUPRENORPHINE/NALOXONE
Early trials comparing buprenorphine to methadone have been critiqued for often employing relatively
low buprenorphine doses and buprenorphine induction approaches that are slower than the current
practice standards.45 Newer studies show that sublingual buprenorphine achieves essentially equivalent
outcomes to methadone when a sufficient dose, appropriate induction rate and flexible dosing are
used.45
Regarding side effects and adverse events, buprenorphine as a partial opioid agonist may be preferable
in terms of reduced overdose potential.45 One recent study of more than 19 million prescriptions over
a six-year period in the United Kingdom found that buprenorphine is six times safer than methadone
in terms of overdose risk.46 Additionally, recent provincial mortality data indicate that methadone is
implicated in approximately 25% of prescription-opioid-related deaths in British Columbia.47 Other
studies have found that methadone has a four-fold higher risk of fatal overdose and a significantly
higher risk of non-medical or other problematic use compared to buprenorphine.48,49 It is also worth
noting that recent reports and a recent expert panel have highlighted the substantial risks of fatal
overdose during methadone treatment initiation.50,51 Buprenorphine has lower potential for respiratory
depression and is well below the threshold lethal dose for opioid-naïve adults compared to standard
methadone doses for opioid use disorder that often exceed the threshold lethal dose.49 Furthermore,
methadone has higher potential for adverse drug–drug interactions with many common medications
(e.g., antibiotics, antidepressants, antiretrovirals), as well as increased risk of cardiac arrhythmias as a
10
result of QT prolongation.52 Patient-reported concerns with
methadone include the potential for tooth decay, which
has been largely under-acknowledged by care providers.53,54
Additionally, because of its partial agonist effect, it is easier
to switch from buprenorphine/naloxone to methadone,
supporting buprenorphine/naloxone as a preferred firstline option in the absence of contraindications.55,56 However,
buprenorphine/naloxone may not be feasible for all patients
due to individual patient factors, including intolerable
symptoms during the prerequisite partial opioid withdrawal
that is required for initiation of buprenorphine/naloxone
treatment, in contrast to methadone treatment.57
6x
Buprenorphine has
a six times greater
safety profile than
methadone in terms
of overdose risk
25%
Consistent with the relative safety profile of buprenorphine/
naloxone in comparison to methadone, it is noteworthy that
Alberta, Ontario, Nova Scotia and Quebec do not require
Methadone is
physicians to have a federal Section 56 exemption from the
implicated in
Controlled Drugs and Substances Act in order to prescribe
1 in 4 prescriptionbuprenorphine/naloxone. In BC, PharmaCare coverage is
opioid-related
undergoing changes to allow access to buprenorphine/
deaths in BC
naloxone without requiring that patients first try methadone.
Historically, coverage has been restricted to patients for
whom methadone treatment was inadequate or contraindicated (e.g., high risk of QTc prolongation,
intolerance or hypersensitivity to methadone).58
Regarding outcomes related to polysubstance use, while opioid agonists are not specifically intended
for the treatment of cocaine addiction, past meta-analyses have shown that effective treatment of
opioid addiction reduces cocaine use in polysubstance-using individuals using both heroin and cocaine.59
To this end, a recent Cochrane review has suggested that methadone and buprenorphine/naloxone are
no different in suppressing cocaine use.44
In terms of cost effectiveness, the Canadian Agency for Drugs and Technologies in Health has recently
noted that, while no Canada-specific studies have been completed, there is evidence that there may
be cost-effective benefits of buprenorphine/naloxone in comparison to methadone.60 Here, the major
potential for cost savings is primarily due to the reduced pharmacy dispensation fees enabled through
more flexible take-home dosing schedules that are safe and feasible with buprenorphine/naloxone.61–64
In terms of gender-related differences, while opioid use is generally more prevalent among males,11 there
do not appear to be significant gender-related differences in outcomes associated with buprenorphine/
naloxone compared to methadone treatment.65,66 Further research is needed since few studies have
examined gender-based outcomes;11 however, forthcoming systematic reviews may provide insight on
potential gender-related differences in outcomes related to opioid agonist therapy.67
11
Table 2. Advantages and disadvantages of methadone
vs. buprenorphine/naloxone
ADVANTAGES
METHADONE
BUPRENORPHINE/NALOXONE
• Potent opioid agonist
• Potentially better treatment retention, particularly for
severely unstable opioid-dependent individuals (e.g.,
injectors) who may be more prone to drop-out
• No precipitated withdrawal/easier to initiate treatment
• Potentially better alternative if buprenorphine was
unsuccessful in relieving withdrawal symptoms, or was
associated with severe side effects
• Approved in Canada for the primary purpose of pain
control (as split dose BID or TID dosing; Health Canada
exemption to prescribe methadone for analgesia also
required)
• Less risk of overdose due to partial agonist effect and
ceiling effect for respiratory depression (in the absence
of benzodiazepines or alcohol)
• Reduced risk of injection, diversion, and overdose due
to naloxone component, allowing for safer take-home
dosing schedules
• Milder side effect profile
• Easier to rotate from buprenorphine/naloxone to
methadone
• More flexible take-home dosing schedules may
contribute to increased cost savings and patient
autonomy
• Shorter time to achieve therapeutic dose (1–3 days)
• Potentially more effective analgesic for treatment of
concurrent pain (however, see disadvantages)
• Fewer drug interactions
• Milder withdrawal symptoms and easier to
discontinue, thus may be a better option for individuals
with lower intensity opioid dependence (e.g., oral
opioid dependence, infrequent opioid users, infrequent
or non-injectors, short history of opioid dependence)
and individuals anticipated to be successfully tapered
off maintenance treatment in a relatively short period
of time
DISADVANTAGES
METHADONE
• Higher risk of overdose, particularly during treatment
initiation
• Generally requires daily witnessed ingestion
• More severe side effect profile (e.g., sedation, weight
gain, erectile dysfunction)
• More expensive if daily witnessed ingestion required
• Longer time to achieve therapeutic dose (> 35 days)
• Higher potential for adverse drug-drug interactions
(e.g., antibiotics, antidepressants, antiretrovirals)
• Higher risk of non-medical or other problematic use
• Increased risk of cardiac arrhythmias as a result of QTc
prolongation
BUPRENORPHINE/NALOXONE
• Potentially higher risk of drop-out
• May cause precipitated withdrawal if induced
inappropriately
• Doses may be suboptimal for individuals with high
opioid tolerance
• May block opioid analgesics used for concurrent pain
treatment
• Not approved in Canada for the primary purpose of
pain control
References
1.
2.
3.
12
Maremmani I, Gerra G. Buprenorphine-based regimens and methadone for the medical management of opioid dependence: selecting the
appropriate drug for treatment. Am J Addict 2010;19:557-68.
Bonhomme J, Shim RS, Gooden R, Tyus D, Rust G. Opioid addiction and abuse in primary care practice: a comparison of methadone and
buprenorphine as treatment options. J Natl Med Assoc 2012;104:342-50.
Centre for Addiction and Mental Health (CAMH). Opioid Dependence Treatment Core Course. Module 2: Treatment Options. Choosing
between methadone and buprenorphine maintenance treatment. May 2015
III Alternative agents
SLOW-RELEASE ORAL MORPHINE *
Since November 2014, slow-release oral morphine (24-hour formulation) has been approved by Health
Canada’s Non-Insured Health Benefits (NIHB) Program for the treatment of opioid use disorder.68 Limited
preliminary evidence suggests that slow-release oral morphine prescribed for maintenance treatment
may reduce illicit opioid use and depressive symptoms.69 However, slow-release oral morphine did not
appear to make a significant difference in treatment retention compared to methadone treatment,
and the risk of adverse events may be greater with slow-release oral morphine.69 Since this preliminary
evidence was published, a number of more recent trials have suggested that slow-release oral morphine
may be a beneficial alternative to methadone treatment. For instance, a recent clinical trial found that
patients treated with slow-release oral morphine demonstrated shorter QTc intervals, decreased heroin
cravings and reduced dysthymic symptoms when compared with patients treated with methadone.70
Another study found that slow-release oral morphine was superior to methadone in terms of reduced
cravings, patient preference and reduced side effects, with similar outcomes to methadone in terms
of drug use and physical and psychological health.71 A multi-centre study of patients intolerant to or
insufficiently responding to methadone found that transitioning patients from methadone to slowrelease oral morphine was relatively easy and well tolerated, and significant advantages were observed
after switching to slow-release oral morphine (e.g., reduced withdrawal symptoms, reduced cravings,
physical and psychological improvements).72
For induction and dosing guidelines for slow-release oral morphine, refer to Appendix 2.
DIACETYLMORPHINE
Among patients who are treatment refractory to methadone, prescription diacetylmorphine (original
trade name Heroin) administered in a clinic setting may be beneficial in terms of reducing illicit substance
use, criminal activity, incarceration, mortality and drop-out.73 While still considered an experimental
treatment in Canada, this treatment is an established standard of care in other settings and generally
involves flexible doses of supplementary oral methadone at the patient’s and clinician’s discretion.
However, because of concerns about possible diversion and higher rates of adverse events (e.g.,
concurrent use of other illicit drugs leading to risk of overdose or seizures, continued use of needles with
attendant risks of venous disease),73 prescription of diacetylmorphine is generally only provided within
highly supervised clinic settings for patients who have repeatedly failed other treatment approaches.
Evaluations of cost effectiveness have suggested that, for patients who responded poorly to methadone
maintenance treatment, diacetylmorphine significantly reduced use of illicit heroin compared to
methadone treatment, and realized significant cost savings primarily related to reduced criminal
activity.74,75 Diacetylmorphine also appears to be associated with slightly superior outcomes related
to social functioning, in comparison with reinitiating methadone treatment in individuals previously
unsuccessfully treated with methadone.73
Note: Slow-release oral morphine refers to the 24-hour formulation of extended-release morphine capsules.
*
13
Comparisons between diacetylmorphine and hydromorphone are currently limited.76,77 Notably,
a small number (n=50) of former patients from the Study to Assess Longer-term Opioid Medication
Effectiveness (SALOME) are maintained on injectable and oral hydromorphone. Other injectable
medications, such as intravenous methadone, have also not been extensively studied.74 Further, no
studies have yet compared injectable diacetylmorphine to treatment with buprenorphine/naloxone.
Although diacetylmorphine has been available for treatment of opioid dependence for several years
in other countries (e.g., United Kingdom, Switzerland and other European countries),78 currently the
treatment is only accessible in Canada through Health Canada’s Special Access Programme.
ANTAGONIST TREATMENTS
Naltrexone is an opioid receptor antagonist that blocks the euphoric effects of opioids at adequate
doses.79 Potential benefits of naltrexone include its ease of administration, its lack of induced tolerance
during long-term treatment, and its pharmacological makeup that is not addictive or prone to abuse.80
However, as an opioid antagonist, naltrexone fully blocks the effects of all opiate medications, including
opioid analgesics prescribed for pain. Additionally, the reduced tolerance to opioids facilitated by the
use of naltrexone may increase the risk of overdose for patients who subsequently relapse to opioid use,
as demonstrated by a non-randomized study of naltrexone-associated mortality rates that were three
to seven times higher than methadone-related mortality rates in Australia.81
Presently, oral naltrexone is not scientifically proven to be superior to other forms of treatment for
opioid use disorder.82 Limited evidence suggests that there are no significant differences in maintenance
treatment using oral naltrexone compared to placebo (except reduced incarceration in two studies),
psychotherapy (based on a single study), benzodiazepines (based on a single study), or buprenorphine
(based on a single study).82 Treatment retention rates appear to be low with oral naltrexone maintenance
treatment (28%).82 However, a recent randomized trial observed fewer positive urine tests among
individuals on oral naltrexone compared to placebo.83
In the United States, extended-release naltrexone is available via monthly intramuscular injection,84
which may promote improved treatment adherence in comparison to oral naltrexone.79 Injectable
naltrexone has demonstrated efficacy compared to placebo in terms of improved retention in treatment,
increased abstinence and decreased opioid cravings.85–87
Presently, extended-release naltrexone is only available in Canada for research purposes or through
Health Canada’s Special Access Programme. However, it is noteworthy to mention that there appears
to be a high level of willingness to take extended-release naltrexone among 52% of opioid users in two
cohort studies of people who use illicit drugs in Vancouver.88
IV Combination approaches and movement between approaches
Due to high rates of polysubstance use (e.g., cocaine and heroin) among opioid-dependent individuals
in Lower Mainland British Columbia, it is important to stress the value of combining opioid agonist
or antagonist treatments with residential treatment, which may allow for psychosocial strategies to
reduce cocaine use (e.g., counselling, contingency management) to be coupled with treatments proven
to promote abstinence from heroin use. This may be particularly valuable given the evidence in support
of changing the environment of individuals who are seeking treatment for concurrent opioid and
14
cocaine dependence, but are severely addicted and actively using.89,90 Of note, methadone doses may
need adjustment as patients transition into and out of cocaine abstinence, as cocaine is a CYP inducer
that can increase metabolism of methadone.91
Regarding transitions between agonist medications, several trials show feasibility when converting to
buprenorphine from low to moderate methadone doses of up to 60–70 mg/day.92 In general, this practice
must be individually tailored, but ideally involves a reduction of the methadone dose to 30 mg per day
or less, if possible, for a minimum of one week prior to inducing buprenorphine. Then, buprenorphine/
naloxone should be introduced according to induction guidelines (see Appendix 1) no sooner than 24
hours after the last dose of methadone.93 When transitioning from methadone doses that are greater
than 70 mg/day, there is an increased risk of significant opioid-withdrawal-related discomfort and
consequent risk of relapse. To mitigate this, adjunct medications and/or inpatient treatment may
be required for rotation to buprenorphine/naloxone from higher doses of methadone.92 Conversely,
rotation from buprenorphine to methadone is relatively uncomplicated, as methadone is a full agonist
and buprenorphine is a partial agonist. Established protocols for rotating between agonist therapies are
available, and some guidance is provided in the College of Physicians and Surgeons of British Columbia’s
Methadone Maintenance Program: Clinical Practice Guideline.5
Given the relatively superior safety profile of buprenorphine/naloxone (in the absence of concurrent
alcohol or benzodiazepine ingestion),61–64 and similar overall costs of methadone versus buprenorphine/
naloxone treatment,94 research has investigated the feasibility of a stepped care strategy involving
initiating agonist treatment with buprenorphine/naloxone followed by methadone among
buprenorphine/naloxone treatment non-responders in comparison to initiating agonist treatment with
methadone.95 This study found that the stepped treatment approach was equally efficacious compared
to optimally delivered methadone maintenance treatment, and concluded that collective data on
the comparatively advantageous safety profile of buprenorphine were sufficient to warrant broader
implementation of buprenorphine as a first-line treatment for opioid use disorder.
There is currently limited evidence to guide strategies for transitioning off agonist therapies among
patients who have achieved long-term abstinence from opioid use. The majority of tapers from
methadone maintenance treatment appear to be unsuccessful (approximately 87%), but there are
increased odds of success when doses are reduced gradually with longer periods of stabilization.96
Specifically, an evaluation of the British Columbia methadone program found a successful taper
completion rate of only 13% across 4,917 treatment episodes, with 35% of patients re-entering
treatment within 18 months and 24% subsequently hospitalized for opioid-related reasons.96 Longer,
more gradual stepped-tapering schedules (e.g., > 52 weeks) in which dosages decrease in no more
than half of the weeks during the total taper period were significantly more likely to result in success.96
Gradual tapering in a therapeutic manner at an appropriate time for the patient may be advantageous,
as demonstrated by a review of voluntary “therapeutic detoxification” patients who demonstrated a
48% pooled abstinence rate compared to a pooled abstinence rate of 22% among non-voluntary, “nontherapeutic detoxification” patients.97
Finally, while there is limited evidence to guide strategies involving multiple attempts using a specific
type of opioid substitution treatment, practitioners should be aware that patients may often require
15
Research
Summary
Defining dosing pattern
characteristics of successful
tapers following methadone
maintenance treatment:
results from a population-based
retrospective cohort study.
Nosyk B, Sun HY, Evans E, et al.
Addiction 2012;107:1621–9.
Ten years: 1996–2006
Outcome:
Sustained successful taper
(no treatment re-entry, opioid-related
hospitalization or death for 18 months
following last dose)
Out of
4917 taper attempts,
646 sustained success (13%)
Factors
For every 1% increase
in adherence
Taper over a long period
(3 months–1 year)
Taper over 12–52 weeks vs < 12 weeks
Plan dose reductions to occur
bi-weekly or monthly
As opposed to more or less frequently
+2%
increased odds
of success
+258%
increased odds
of success
+61%
increased odds
of success
several attempts with a certain therapy before they successfully achieve opioid abstinence, or before
an alternative treatment strategy is implemented.
V Psychosocial supports
Recent meta-analyses and randomized controlled trials have suggested that there does not appear
to be an additional benefit to more structured psychosocial treatment interventions (e.g., cognitive
behavioural therapy, contingency management) in conjunction with standard agonist maintenance
treatments in terms of retention in treatment, abstinence from opioid use during and by completion of
treatment, treatment compliance, psychiatric symptoms, depression or treatment completion rates,
when compared to maintenance treatment with standard medical management involving routine
counselling.98–100 Further research is required to assess the effect of psychosocial treatments versus
psychosocial supports (e.g., to facilitate housing) on outcomes that may indirectly reduce drug use in
the long term (e.g., social assistance, increased social support, vocational training).98
While the evidence for structured psychosocial treatments is poor, the addition of evidence-based
psychosocial supports in combination with pharmacological opioid agonist treatment and standard
medical management may be helpful in supporting overall recovery from opioid addiction in terms of
improving individuals’ psychosocial circumstances and other survival needs (e.g., housing). Psychosocial
interventions directly aimed at maintaining abstinence may also play a role in post-detoxification
relapse prevention, but further research is needed in this area. Regardless, attention to assessing,
treating and monitoring emotional and mental health is an essential component of care for patients
with opioid use disorder, especially given the high prevalence of concurrent medical and mental health
diagnoses among this population.101–103 Therefore, psychosocial supports may be routinely offered to
patients in conjunction with pharmacological treatment.104
16
Expert guideline
Summary of recommendations
Recommendation
For more
Quality of
Strength of
information
evidence* recommendation* see page…
Approaches to avoid
1. Withdrawal management alone (i.e., detox
without transition to longer term treatment) is not
recommended, since this approach has been associated
with elevated rates of HIV infection and overdose death.
⊕⊕⊕
Moderate
Strong
6
2. Initiate opioid agonist treatment with buprenorphine/
naloxone whenever feasible to reduce toxicities and
facilitate safer take-home dosing.
⊕⊕⊕⊕
High
Strong
10
3. Initiate opioid agonist treatment with methadone
when treatment with buprenorphine/naloxone is not
preferable (e.g., challenging induction, high risk for
drop-out).
⊕⊕⊕⊕
High
Strong
9
⊕⊕⊕
Moderate
Strong
6–7
⊕⊕⊕⊕
High
Strong
14
6. For individuals with successful and sustained response to
⊕⊕⊕
methadone desiring treatment simplification, consider
Moderate
transition to buprenorphine/naloxone.
Strong
14
7. For individuals with successful and sustained response
to agonist treatment desiring medication cessation,
consider slow taper over 12 months.
⊕⊕⊕
Moderate
Strong
6
8. Psychosocial supports may be routinely offered in
conjunction with pharmacological treatment.
⊕⊕⊕
Moderate
Conditional
16
⊕⊕
Low
Weak
6, 14
Possible first-line treatment options
4. When opioid withdrawal is being medically supervised,
this can generally be safely done on an outpatient
rather than inpatient basis but should include ongoing
addiction treatment.
Adjunct or alternative treatment options
5. For individuals responding poorly to buprenorphine/
naloxone, transition to methadone.
9. For patients wishing to avoid initial treatment with
an opioid agonist therapy, provide outpatient opioid
agonist taper (preferably methadone or buprenorphine/
naloxone), with subsequent immediate referral to
intensive outpatient or residential addiction treatment.
Oral naltrexone can be considered as an adjunct in this
context.
* GRADE criteria were used to ascertain and describe the quality of evidence (possible categories include: high, moderate,
low, very low) and strength of recommendation (possible categories include: strong, conditional, weak).1
17
Patients presenting with opioid use disorder can be offered a range of treatment options based on
their clinical presentation with respect to their addiction severity, comorbidities, present psychosocial
circumstances (e.g., homelessness), as well as the accessibility of possible treatment options. While this
guideline supports the diversity of possible treatments available for individuals presenting with opioid
use disorder, it strongly recommends against strategies involving withdrawal management alone,
since this approach has been associated with elevated rates of HIV infection and overdose deaths in
comparison to providing no treatment.13,14
Therefore, a possible option is to engage patients in outpatient opioid maintenance (preferably
methadone or buprenorphine/naloxone) to achieve stability and retention, followed by a very slow
opioid agonist taper under close supervision aimed at continuing opioid maintenance if relapse risk
emerges, with ongoing intensive outpatient or inpatient addiction treatment. In this context, while
residential treatment programs have not been rigorously evaluated, given the evidence in support
of changing the environment of individuals who are severely addicted and actively using opioids,89,90
referral to a residential treatment facility is a preferred option for individuals willing to pursue a tapered
agonist treatment option. With respect to this recommendation, separate initiatives will need to be
undertaken to improve the accessibility of the quality of residential treatment, consistent with past
reports.105 Given the evidence that opioid tapers result in a high rate of relapse, this option should only
be recommended to individuals viewed to have a high chance of successful recovery without long-term
agonist treatment.
A second first-line option would be the initiation of opioid agonist treatment with either methadone or
buprenorphine/naloxone. Patients do not have to go through a trial of medically managed withdrawal
and subsequent relapse in order to be candidates for opioid agonist maintenance. The committee
recommends, for the reasons articulated above, that buprenorphine/naloxone be given consideration
as a first-line agent in instances where induction onto buprenorphine/naloxone is feasible and does not
promote barriers to retention. Guidance for take-home dosing is provided in Appendix 3. Induction and
dosing guidelines for buprenorphine/naloxone are provided in Appendix 1. As is the case throughout this
guideline, the choice of treatment should be determined on a case-by-case basis, taking into account
the patient’s history and commitment to a particular management strategy, and weighing the risks
and benefits of treatment options. In cases where both methadone and buprenorphine/naloxone are
suitable options, buprenorphine/naloxone may be considered as a first-line treatment.
Alternatively, methadone is an acceptable first-line option in cases where it will be challenging to
induce onto buprenorphine/naloxone or where loss to follow-up could be highly problematic from
the perspective of the individual (e.g., an individual for whom precipitated withdrawal or treatment
retention is a major concern) or of public health (e.g., risk of HIV transmission). For instance, methadone
may be preferable for severely chaotic patients or individuals with higher opioid tolerance due to highintensity use, for whom buprenorphine/naloxone doses may be suboptimal and may lead to poorer
retention outcomes.106 For induction and dosing guidelines, practitioners should refer to the College of
Physicians and Surgeons of BC guideline.5
For individuals responding poorly to either methadone or buprenorphine/naloxone despite multiple
attempts and despite efforts to address barriers to successful treatment, consideration may be paid
18
to attempting treatment with an alternative first-line agent. As described above, for reasons of safety
with respect to diversion as well as its side effect profile, buprenorphine/naloxone has a number of
advantages over methadone, and transitioning from methadone to buprenorphine/naloxone or
initiating with buprenorphine/naloxone is recommended for these reasons. Certainly, for a client who
struggles with ongoing illicit opioid use while on adequately dosed buprenorphine/naloxone, methadone
would be an appropriate second-line option. For clients wishing to taper off agonist treatment due to
dissatisfaction with methadone maintenance treatment related to the inconvenience of daily witnessed
ingestion requirements, difficulty obtaining take-home or “carried” doses, and other common concerns,
transitioning from methadone to buprenorphine/naloxone may be advantageous.45,55
Alternatively, slow-release oral morphine (24-hour formulation) is increasingly being used for individuals
unsuccessfully treated with first-line options. While completed systematic reviews of slow-release
oral morphine have provided mixed evidence, more recent studies have demonstrated a good safety
profile and high degree of patient satisfaction.69–72 To limit potential for diversion, it is recommended
that slow-release oral morphine be provided via daily witnessed ingestion, preferably administered by
opening the extended-release capsules and sprinkling the enclosed pellets (e.g., on top of apple sauce)
in order to reduce the risk of diversion. Dosing guidelines for slow-release oral morphine are provided
in Appendix 2.
As described above, a number of settings have initiated diacetylmorphine programs, provided via
witnessed injection at specialized clinics for patients who respond poorly to methadone maintenance
treatment. Unfortunately, at present, within VCH there is only one clinic offering this treatment, and for
regulatory, legal and cost-constraint reasons, this treatment is not widely available. Providing guidelines
for the safe prescribing of diacetylmorphine is outside the scope of this guideline.
Regarding standardized psychosocial treatments (e.g., cognitive behavioural therapy) coupled
with pharmacotherapies, the evidence does not suggest clear benefits over standard medical
management traditionally provided with opioid agonist therapies. However, this does not suggest
that pharmacotherapy should be offered in isolation, but rather that, provided along with opioid
agonist treatments, evidence-based psychosocial supports focused on psychosocial circumstances
(e.g., housing, vocation) and other survival needs (e.g., social assistance) may be helpful in supporting
recovery from opioid addiction. Psychosocial interventions directly aimed at maintaining abstinence
may also play a role in post-detoxification relapse prevention, but further research is needed in this
area. Ongoing assessment, treatment and monitoring of emotional, medical and mental health is an
important component of treating opioid use disorder.
Finally, these interventions may benefit from additional harm reduction interventions, including
education about sterile syringe use and take-home naloxone for reducing the risk blood borne infections
or the risk of fatal overdose among high-risk patients or patients with ongoing opioid use.17,18
Opioid use disorder is a chronic disease that is associated with significantly elevated rates of morbidity
and mortality. It is important that all patients are offered evidence-based treatment for their illness.
Patients and clinicians may work toward finding appropriate treatment plans that can be adjusted along
a continuum in order to promote optimal health and wellbeing.
19
Appendix 1: Induction and dosing guidelines for buprenorphine/naloxone
1.Assessment
Common contraindications
•
Buprenorphine/naloxone (bup/nlx) allergy
•
Pregnancy (refer to specialist care)
•
Severe liver dysfunction (caution if liver enzymes > 3–5 times normal upper limit)
Baseline assessment
•
Diagnosis of opioid use disorder
•
Urine drug test (positive for opioids) and other laboratory tests
2.Induction
Preparation
a. If patient is on methadone, aim to taper to a methadone dose of ≤ 30 mg per day (or at least
< 60 mg per day) for a minimum of 6–7 days prior to bup/nlx induction. Wait at least 24 hours
after the last dose of methadone before beginning bup/nlx induction, as per Day 1 guidelines
below.
b. For the patient not on methadone, instruct patient to discontinue opioid use 12–24 hours prior
to the morning of the first day of scheduled bup/nlx induction.
c. Emphasize to patient that opioid use within 12–24 hours of induction may exacerbate rather
than alleviate withdrawal symptoms.
d. Ensure patient is aware not to drive or operate heavy machinery during induction.
Day 1
a. Plan induction of bup/nlx for weekday morning dosing, allowing for reassessment in the afternoon.
b. At the time of the first dose of bup/nlx, the risk of precipitated withdrawal is lower if the
patient has signs of at least moderate opioid withdrawal. A Clinical Opiate Withdrawal Scale
(COWS) score greater than 12 at the time of induction is associated with less risk of precipitated
withdrawal. For COWS < 12, consider postponing first dose of bup/nlx until later in the day or the
following day, when the patient is demonstrating more severe withdrawal.
c. The most common starting dose is 4/1 mg sublingual bup/nlx when COWS > 12 and no longacting opioid has been used recently. This dose may be lowered to 2/0.5 mg if there is a
high risk of precipitated withdrawal, or it may be increased up to 6/1.5 mg if the patient is
experiencing severe withdrawal symptoms at the time of the induction. Witnessed ingestion
is recommended, to ensure that the tablet is appropriately administered and dissolved
sublingually, though take-home induction is an option (instruct patient to keep the tablet in
their mouth until it dissolves, which may take up to 5 minutes).
20
d. Since precipitated withdrawal can become evident within the first few hours after the first dose
of bup/nlx, reassess after 2–3 hours from the time of first dose.
•
If withdrawal symptoms are adequately relieved after 2–3 hours, the induction for Day 1 is
complete. Prescribe the same total dose (as administered on Day 1) for the following day.
•
If withdrawal symptoms are not adequately relieved, consider additional dose(s). A maximum
total of 12/3 mg bup/nlx may be administered on Day 1 depending on the individual
patient’s requirement, though newer U.S. recommendations allow for 16/4 mg on Day 1.
If uncertain about the need for an additional dose, consider prescribing 1–2 2/0.5 mg takehome tablets for withdrawal that may occur later in the evening.
•
If withdrawal symptoms are adequately relieved with additional dose(s), then the induction
for Day 1 is complete. Prescribe the same total dose (as administered on Day 1) for the
following day.
•
If withdrawal symptoms are not adequately treated with additional dose(s), manage
withdrawal symptoms symptomatically (see step e) and continue induction the following
day.
e. In some cases, short-term symptomatic relief may be offered by prescribing a non-opioid, nonsedative agent. For example:
•
Clonidine (0.1–0.2 mg q4h prn for < 12 hours)
•
PRN anti-emetic, antidiarrheal, NSAID, acetaminophen
Days 2 onward
a. If no withdrawal symptoms since last dose, continue a once-daily dose equal to the total
amount of bup/nlx administered on the previous day titrating up as needed in subsequent days
aiming for a target dose of 16/4 mg or greater.
b. If withdrawal symptoms present since last dose, administer dose equal to the total amount
administered on previous day, plus an additional 4/1 mg bup/nlx.
•
If symptoms relieved after 2–3 hours, prescribe this total dose for the next day.
•
If symptoms not relieved after 2–3 hours, administer a second additional 4/1 mg dose of
bup/nlx (to a maximum total of 16/4 mg bup/nlx on Day 2). If symptoms relieved after 2–3
hours after the second additional dose, prescribe this total daily dose for the following day.
If symptoms not relieved 2–3 hours after the second additional dose, manage withdrawal
symptomatically for the remainder of Day 2.
c. On the following induction days, if withdrawal symptoms persist, continue dose increases as per
the above schedule. Titrate as needed (by 2/0.5 to 4/1 mg bup/nlx at a time), up to a maximum
total of 24/6 mg bup/nlx per day (as stipulated by Health Canada; however, U.S. guidelines state
that some patients may require doses up to 32/8 mg bup/nlx per day). An optimal maintenance
dose is achieved when the patient is able to sustain an entire 24-hour dosing interval with no
withdrawal symptoms and no medication-related intoxication or sedation (hold bup/nlx dose
if intoxicated or sedated). Target dose is generally 12/3 mg to 16/4 mg bup/nlx per day by the
end of first week.
21
d. Once optimal dose achieved, continue to follow up once or twice per week (or more frequently,
as needed) to assess for dose effectiveness and side effects.
3.Maintenance
a. Once clinical stability is achieved at a maintenance dose, frequency of follow-up may be
gradually reduced. Once stable, continue to assess at least every 1–2 weeks with the option to
decrease follow-up visits as increasing stability is achieved.
b. Follow-up assessments: adequacy of dosage, side effects, substance use (via urine testing,
when indicated), psychosocial functioning
c. For clinically stable patients at stable doses, consider:
•
Alternate day dosing (e.g., single dose on Sundays and double doses on Mondays,
Wednesdays and Fridays)
•
Gradually increasing take-home doses. Generally, consideration can be given to
witnessed dosing for at least 2 months after a stable dose is achieved, although this can
be individualized with carry doses offered immediately, as is the standard of care in the
U.S. Always educate patients on risks to self and others when giving take-home doses.
If diversion or misuse is suspected, consider reducing or eliminating take-home dosing
and altering the dose to minimize risk of opioid toxicity once daily witnessed ingestion is
resumed.
d. For missed doses (when other opioids have not been used) ≤ 5 days, resume previous dose. For
missed doses ≥ 6 days, a conservative dosing guideline is:
Buprenorphine
dose
Number of
missed days
Start new
dose at...
2–4 mg
6+ days
2–4 mg
6–8 mg
6+ days
4 mg
> 8 mg
6–7 days
8 mg
> 8 mg
> 7 days
4 mg
If ≥ 6 days have been missed and patient has returned to illicit opioid use, reinduction may
be necessary.
References:
1.
2.
3.
22
Centre for Addiction and Mental Health. Buprenorphine/
Naloxone for Opioid Dependence: Clinical Practice Guideline.
November 2012. Accessed online on March 15, 2015 at
knowledgex.camh.net/primary_care/guidelines_materials/
Documents/buprenorphine_naloxone_gdlns2012.pdf
Center for Substance Abuse Treatment. Clinical Guidelines for
the Use of Buprenorphine in the Treatment of Opioid Addiction.
Treatment Improvement Protocol (TIP) Series 40. DHHS
Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse
and Mental Health Services Administration, 2004.
Farmer CM, Lindsay D, Williams J, Ayers A, Schuster J,
Cilia A, Flaherty MT, Mandell T, Gordon AJ, and Stein BD. Practice
4.
5.
Guidance for Buprenorphine for the Treatment of Opioid Use
Disorders: Results of an Expert Panel Process. Substance Abuse
2015;36:209–216.
Casadonte PP, Sullivan MA. 2013. Buprenorphine induction.
Providers’ clinical support system for medication assisted
treatment, PCSS guidance. August 9, 2006 (Updated
November 27, 2013). Available at: pcssmat.org/wp-content/
uploads/2014/02/PCSS-MATGuidanceBuprenorphineInduction.
Casadonte.pdf
Gunderson EW, Levin FR, Rombone MM, Vosburg SK, Kleber
HD. Improving Temporal Efficiency of Outpatient Buprenorphine
Induction. Am J Addictions 2011; 20(5):397–404.
Appendix 2: Dosing recommendations for slow-release
oral morphine (SROM)
Slow-release oral morphine (SROM) — which refers to the 24-hour formulation of the extended-release
capsules—is a potential option for individuals who respond poorly to other maintenance treatments.
While these guidelines are based on the protocols used in several randomized controlled trials that
demonstrated efficacy of SROM for opioid dependence, it is important to note that there is currently no
established “best” clinical treatment protocol for SROM maintenance, requiring diligent measures to
avoid overdose (e.g., close monitoring of initiation and stabilization in a specialized treatment setting,
appropriate titration, specialist referral).
1.Eligibility
These recommendations are most applicable to patients who are:
•
Adults (≥ 18 years) with opioid use disorder
•
Switching to SROM from methadone or another opioid
•
Not pregnant or breastfeeding
2.Summary
•
SROM maintenance is administered via once-daily oral doses.
•
SROM is released over 24 hours. Peak plasma levels are achieved within 2–6 hours.
•
Daily witnessed ingestion via opening capsules and sprinkling the enclosed pellets
(e.g., on top of apple sauce) is strongly recommended to avoid diversion.
3.Assessment and monitoring
•
Treatment efficacy: urinalysis, heroin and other drug use, cravings, withdrawal
•
Psychosocial: assess for depression, anxiety at baseline and every 1–2 months thereafter
•
Adverse effects: most common are stomach cramps, abdominal pain, headache, dizziness,
hyperhidrosis, toothache, dry mouth, constipation, frequent urination, nausea, vomiting,
insomnia
4.Induction
•
No wash-out of previous treatment is required (to minimize potential for withdrawal
symptoms). Withdrawal symptoms may recur temporarily during the switch-over period.
•
Begin with a 1-week adjustment/titration phase aiming to achieve a stable daily dosage.
•
Switch from methadone oral solution to SROM. Generally a switch will require an ultimate dose
of 1:6–1:8, but we suggest beginning with a 1:4 induction with titration upwards based on
withdrawal scores and craving. Titrate upward in incremental doses according to withdrawal
scores.
23
There are a variety of dosing schedules described in the literature. Examples include:
Example 2
Example 1
MMT to SROM
Daily lower frequency heroin use
• Begin with estimated methadone-to-SROM
dose equivalence of 1:4, then increase
incrementally according to withdrawal
scores
• Day 1: 30–60 mg SROM
• Titrate dose upward according to
individual patient’s withdrawal scores
According to existing literature, the average (mean) SROM dose ranges from 235–791 mg/day.
The full range of SROM doses described in the literature is 60–1200 mg/day.
5.Maintenance
• The goal is to stabilize the once-daily dose to a maximum of 1200 mg/day. Currently, there is no
published literature to guide treatment decisions beyond 36 weeks (8 months).
Note, for individuals on SROM, urine drug screens will be positive for morphine metabolite meaning it
may be difficult to distinguish on UDS between illicit heroin or supervised SROM use.
References:
1.
2.
3.
24
Beck T, Haasen C, Verthein U, et al. Maintenance treatment
for opioid dependence with slow-release oral morphine: a
randomized cross-over, non-inferiority study versus methadone.
Addiction 2014;109:617-26.
Eder H, Jagsch R, Kraigher D, et al. Comparative study of the
effectiveness of slow-release morphine and methadone for
opioid maintenance therapy. Addiction 2005;100:1101-9.
Ferri M, Minozzi S, Bo A, et al. Slow-release oral morphine
as maintenance therapy for opioid dependence. Cochrane
Database Syst Rev 2013;6:CD009879.
4.
5.
Hammig R, Kohler W, Bonorden-Kleij K, et al. Safety and
tolerability of slow-release oral morphine versus methadone
in the treatment of opioid dependence. J Subst Abuse Treat
2014;47:275-81.
Jegu J, Gallini A, Soler P, et al. Slow-release oral morphine for
opioid maintenance treatment: a systematic review. Br J Clin
Pharmacol 2011;71:832-43.
Appendix 3: Take-home dosing recommendations for oral agonist therapy
Take-home dosing of oral agonist therapy may be beneficial in terms of improved treatment retention,
increased patient autonomy and flexibility, positive reinforcement of abstinence, decreased treatment
burden, and decreased costs related to daily witnessed ingestion.1 This must be balanced against patient
and public health risks.
1.Methadone maintenance treatment
Specific instructions regarding the provision of take-home dosing may be found in the College of
Physicians and Surgeons of British Columbia’s Methadone Maintenance Program: Clinical Practice
Guideline.2
2.Buprenorphine/naloxone
Take-home dosing of buprenorphine/naloxone may be provided at any time at the discretion of the
treating physician. Previous research has demonstrated some improved patient outcomes when
buprenorphine/naloxone is initially provided via daily witnessed ingestion before individuals are
able to graduate to receiving take-home doses.3–6 Generally, take-home dosing can be provided for
one to two weeks’ worth of medication at a time.
Considerations for restricting patients to daily witnessed ingestion of buprenorphine/naloxone can
include:1,7,8
•
Improved patient-clinician therapeutic relationship, promotion of patient safety and treatment
compliance via increased engagement with health care provider (i.e., physician, pharmacist) in
early weeks of recovery
•
Homelessness or other reasons for inability to safely store medication
•
Evidence of patient diversion of medication
•
Ongoing substance use, especially benzodiazepines, alcohol or other sedatives
•
Length and track record of clinic attendance
•
Severe behavioural issues, cognitive impairment or unstable mental health
It is the responsibility of the treating physician to decide when take-home dosing is advisable and
whether ongoing daily witnessed ingestion is optimal from a patient and public safety perspective.
Generally, Canadian guidelines and those from some other settings (e.g., Australia) recommend
that initial daily witnessed ingestion of buprenorphine/naloxone be followed by a gradual increase
in take-home doses, up to one to two weeks’ worth of medication at a time between observed
doses, according to individual risk assessments.1,9,10 Notably, U.S. guidelines are much more flexible,
with recent federal amendments removing maximum take-home dose restrictions (previously
restricted to a one-month take-home supply) for buprenorphine/naloxone, due to its lower risk for
abuse and adverse events compared to methadone.7 While there are no established protocols for
take-home dosing of buprenorphine/naloxone, clinicians may consider the following:
25
•
Health Canada recommends that all doses of buprenorphine/naloxone should be observed for
at least the first two months of treatment, with the exception of weekends and holidays. Takehome doses may be prescribed earlier than two months, provided that:
1. the patient has explicitly consented to receiving this “against label” prescription, and has
been made aware of the potential risks to self and others; and
2. the physician has clearly documented these discussions and the clinical rationale for takehome dosing.1
•
As with methadone maintenance treatment, the provision of take-home doses of buprenorphine/
naloxone in response to negative random urine drug screen results may be an effective method
of reinforcing abstinence.1,4
Consideration can also be given to providing take-home medication during buprenorphine/naloxone
induction, when multiple same-day visits may not be possible or practical.11,12 Specifically, takehome doses may be prescribed in combination with witnessed doses, while ensuring that patients
are provided with detailed instructions and telephone numbers for patient support. For example,
following an initial 4 mg starting dose in the clinic, a patient who may not be able to return for
reassessment that same day may be given a second take-home dose of 4 mg to be taken in the event
of recurrence of withdrawal symptoms, in order to help decrease the likelihood of illicit opiate use.
3.Slow-release oral morphine (24-hour formulation)
It is recommended that similar restrictions for daily witnessed ingestion be implemented as per the
College of Physicians and Surgeons of British Columbia’s current recommendations for methadone
maintenance treatment.2
References:
1.
2.
3.
4.
5.
6.
7.
26
Centre for Addiction and Mental Health. Buprenorphine/
Naloxone for Opioid Dependence: Clinical Practice Guideline.
November 2012. Available at: knowledgex.camh.net/primary_
care/guidelines_materials/Documents/buprenorphine_
naloxone_gdlns2012.pdf
College of Physicians and Surgeons of British Columbia.
Methadone Maintenance Program: Clinical Practice Guideline.
February 2014 (Revised July 2014). Accessed online on 13 Jan
2015 at: www.cpsbc.ca/programs/bc-methadone-program/
methadone-maintenance
Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus
buprenorphine-naloxone maintenance therapy for opioid
dependence. N Engl J Med 2006;355:365-74.
Gunderson EW, Wang XQ, Fiellin DA, Bryan B, Levin FR.
Unobserved versus observed office buprenorphine/naloxone
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2010;35:537-40.
Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home
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Center for Substance Abuse Treatment. Clinical Guidelines for
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Substance Abuse and Mental Health Services Administration
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